Multilayer galantamine delivery system with barrier against reservoir material flow

ABSTRACT

A multilayered drug delivery system with a barrier suitable for delivery of galantamine through an individual&#39;s body surface. By placing a barrier between two adjacent layers, unintended galantamine flow due to migration of a drug matrix between the adjacent matrix layers in the system to a patient is avoided.

CROSS REFERENCE TO RELATED U.S. APPLICATION DATA

The present application claims the benefit of provisional application60/680,905 filed May 13, 2005 and provisional application 60/790,236filed Apr. 7, 2006, both of which are incorporated by reference herein.

TECHNICAL FIELD

This invention relates to a multilayer drug delivery system. Moreparticularly, the invention relates to a multilayer system that includesa barrier that separates layers in the system used in transdermal drugdelivery.

BACKGROUND

Transdermal devices for the delivery of biologically active agents havebeen used for maintaining health and treating therapeutically a widevariety of ailments. For example, analgesics, steroids, etc., have beendelivered with such devices. Such transdermal devices include patches inwhich a biologically active agent is delivered to the body tissuepassively without the use of an additional energy source. Many suchdevices have been described, for example, in U.S. Pat. Nos. 3,598,122,3,598,123, 4,379,454, 4,286,592, 4,314,557, 4,568,343, and U.S.Publication No. 20030026829, all of which are incorporated herein byreference.

A transdermal patch is typically a small adhesive bandage that containsthe drug to be delivered. A simple type of such transdermal patches isan adhesive monolith including a drug-containing reservoir disposed on abacking. The reservoir is typically formed from a pharmaceuticallyacceptable pressure sensitive adhesive. In some cases, the reservoir canbe formed from a non-adhesive material, with the skin-contacting surfacehaving a thin layer of a suitable adhesive. The rate at which the drugis administered to the patient from these patches can vary due to normalperson-to-person and skin site-to-skin site variations in thepermeability of skin to the drug.

More complex patches can be a multilaminate or can include drugreservoir layers in the patches. Exemplary transdermal drug deliverysystems are illustrated by the embodiments shown in FIGS. 1, 2 and 3. Asshown in FIG. 1, a transdermal monolithic patch 1 according to thisinvention has a backing layer 2, a drug reservoir 3 disposed on thebacking layer 2, and a peelable (removable) protective layer 5. In thereservoir 3, which can be a layer, at least the skin-contacting surface4 is an adhesive. The reservoir is a matrix (carrier) that is suitablefor carrying the pharmaceutical agent (or drug) for transdermaldelivery. The matrix is a structure in which the drug is or can bedissolved. Preferably, the whole matrix, with drugs and other optionalingredients, is a material that has the desired adhesive property. Thereservoir 3 can be either a single phase polymeric composition or amultiple phase polymeric composition. In a single phase polymericcomposition the drug and all other components are present atconcentrations no greater than, and preferably less than, theirsaturation concentrations in the reservoir 3. This results in acomposition in which no undissolved components are present. Thereservoir 3 is formed using a pharmaceutically acceptable polymericmaterial that can provide adhesive property for application to the bodysurface. In a multiple phase polymeric composition, at least onecomponent, for example, a therapeutic drug, is initially present inamount more than the saturation concentration. In some embodiments, morethan one component, e.g., a drug and a permeation enhancer, is presentin amounts above saturation concentration. In the embodiment shown inFIG. 1, the adhesive acts as the reservoir and includes a drug.

In the embodiment shown in FIG. 2, the reservoir 3 is formed from amaterial that does not have adequate adhesive properties to maintain thepatch on the skin for the desired period. In this embodiment of amonolithic patch 1, an overlaying adhesive layer 6 is included to attachthe reservoir 3 to the skin. The reservoir 3 may be a single phasepolymeric composition or a multiple phase polymeric composition asdescribed earlier, except that it may or may not contain an adhesivewith adequate adhesive bonding property for skin. The overlayingadhesive layer 6 can also contain the drug and permeation enhancer, aswell as other ingredients. In this design, however, the drug in thereservoir 3 would have to pass through the adhesive layer 6 to reach thebody surface. The solubility of the adhesive layer may not be suitablefor the rate of delivery desired.

In an alternative prior device shown in FIG. 3, an adhesive layer 6overlays the protective layer 2 and the reservoir 3 so as to adhere tothe body surface with the overhanging portion 8 of the adhesive layer 6.A backing layer 10 protects the adhesive overlay layer 6.

Although the transdermal delivery of therapeutic agents has been thesubject of intense research and development for over 30 years, only arelatively small number of drug molecules are suitable for transdermaldelivery. For effective delivery, a delivery rate that istherapeutically effective is needed. Many factors affect the deliveryrate. The thickness and concentration of the drug reservoir and thelayers adjacent to the drug reservoir, as well as the rheologicalproperties of the layers are some of these factors.

Often, due to the chemical as well as physical characteristics (e.g.,rheological parameters), a system may change over time, e.g., during aperiod of storage. For example, the matrix formulations typically coldflow over time. The extent of cold flow can be affected by the fluidcharacteristics of the reservoir matrix, as well as physical forces thatmay be applied on the device, for example, by the protective pouchpressing on the reservoir. Typically, the drug delivery patches are madeby cutting multiple layers simultaneously, resulting in the layershaving the same planer size and their edges being flush on the side ofthe patch. Thus, for typical patch devices like those shown in FIG. 1 toFIG. 3, reservoir material may migrate along the side of the patch. Inthe cases of FIG. 1 and FIG. 2 the reservoir material may migrate andcome into contact with the inside of a protective pouch, which is usedfor protecting the device and may not be chemically compatible with thedrug reservoir. In the case of FIG. 3, the reservoir material maymigrate to the adhesive layer 6. The adhesive layer 6 often is permeableto the drug in the reservoir, allowing the drug to diffuse throughout.If the adhesive contains chemicals to which the reservoir is permeable,the chemicals may migrate into the reservoir. Such unintended chemicalmigration is highly undesirable as it will reduce the concentration ofthe active agent in the drug reservoir and thus reduce the deliveryrate, and may lead to contamination in the drug reservoir. Further, theinside surface of the protective pouch may contain heat seal polymers,which may allow drug migration from the reservoir. In the cases of FIG.1 and FIG. 2, cold flow might still cause drug loss by diffusion to theheat seal material in the inside of the pouch.

Galantamine, also called galanthamine, has the structure C₁₇H₂₁NO₃, andis chemically named4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro(3a,3,2-ef)(2)benzazepin-6-ol.The preparation and pharmacological activity of galantamine have beendescribed in U.S. Pat. Nos. 5,877,172; 6,194,404; 6,335,328; 6,573,376;and 6,617,452. Further, transdermal delivery of galantamine has beenmentioned in U.S. Pat. Nos. 5,700,480; 5,932,238; as well as U.S. PatentPublication No. 20040192683. Galantamine is one of the reversibly actingcholinesterase inhibitors. It is reported to have effects similar tothose of physostigmine and neostigmine but presents a lower risk oftoxicity as physostigmine or neostigmine. Galantamine has been reportedto be useful for treatment of the narrow-angle glaucoma and, as antidoteafter curare applications, treatment of dementia, Alzheimer's diseaseand the treatment of alcohol dependence.

However, to be effective in a multiple day patch, galantamine contentneeds to be high. For example, a drug loading of 10 wt % cannot supporta multi-day system without the introduction of a secondary drugreservoir or very thick adhesive layer. Prior art references ontransdermal galantamine delivery do not teach systems that permits highgalantamine solubility and flux rates. For example, U.S. Pat. No.5,700,480 describes a flux that if delivered from a reasonably smallpatch would be low for effective therapy of Alzheimer's disease. Theflux reported there was on mice skin, which tends to have higherpermeability than human skin. For delivery to human, better design toimprove galantamine loading and permeation will be required. Highgalantamine and enhancer contents tend to tackify and soften thereservoir, respectively, thereby increasing the risk of cold flow.

Thus, a transdermal galantamine delivery device with good drug loadingand sufficient flux is needed for effective therapy of Alzheimer'sdisease from a reasonably sized patch. Similarly, there is a need forgalantamine delivery device for therapy of other ailments sincegalantamine has been reported to be effective in therapy on dementia,smoking, alcoholism, etc. There continues to be a need for improveddelivery of galantamine, especially sustained delivery over a period oftime. What is needed is a multilayer galantamine delivery system that ismore stable overtime, thus ensuring reliable, predictable delivery ofthe drug, even for systems that may have been stored for a long periodof time.

SUMMARY

The present invention provides a method and a device for delivery ofgalantamine for therapeutic effects, especially delivery of galantamineto a subject transdermally through the skin or other body surfaces. Anindividual can wear the device adhesively over an extended period oftime.

In one aspect, the present invention provides a device foradministration of galantamine to an individual at a therapeuticallyeffective rate through a body surface. The device has a reservoir havinga matrix including galantamine in the matrix; a backing layer attachedto the reservoir and is substantially impermeable to galantamine. Thereis also a second matrix in which galantamine is diffusible and a barrierlayer disposed between the reservoir and at least part of the secondmatrix. The barrier layer has a barrier outer perimeter and thereservoir has a reservoir outer perimeter such that the barrier layerouter perimeter is larger than the reservoir outer perimeter. Thebarrier layer is made of a material that is substantially impermeable,preferably completely impermeable, to galantamine.

The barrier layer, having an outer perimeter larger than the outerperimeter of a drug reservoir attached to it, advantageously preventsany migration of the drug reservoir from crossing over to anther matrixlayer.

The present invention is particularly useful in transdermal systems inwhich the reservoir material (matrix) is a highly viscous fluid i.e.will deform under stress as may occur during processing or extendedstorage, and it may flow when pinched or pressed. In a method of makinga patch with the reservoir matrix on the backing layer in which the twoare cut to a desired size and shape (e.g., by die cutting), in which atleast one (sometimes all) edge of the backing is flush with at least oneedge of the reservoir matrix, some of the reservoir matrix material mayadhere to the edges of the backing layer. The edges of the reservoir andthe backing layer are flush in FIG. 2 and FIG. 3. For example, when thecutting is done by cutting through the reservoir (matrix) and then thebacking layer, the reservoir matrix, having a creep compliance thatmakes it somewhat flowable, will be pinched with the backing layer alongthe edges and some of the reservoir matrix material will be carried bythe cutter to adhere to the edge (or edges) of the backing layer. Whenthe resulting backing layer with reservoir matrix is attached to anadhesive (either that of a overlay or another reservoir matrix), thereservoir matrix material that adheres to the edge of the backing layermay touch the adhesive and allow drug to migrate thereto. Even if thetwo materials are only in close proximity but do not actually touch whenthe system is freshly made, with time, cold flow of the reservoir matrixor the adhesive will most likely allow them to touch and cause drugmigration. Thus, the barrier layer of the present invention providessignificant benefit to prevent the reservoir matrix and the adhesivefrom touching and drug migration therebetween.

In an aspect, the barrier layer is a frame-shaped layer. Theframe-shaped layer has a window through which a matrix layer having someadhesive property can attach to a different layer, for example, thebacking layer of another matrix layer. Since the reservoir material isfluid, this window enables the reservoir layer to be smaller in outerperimeter than the barrier frame and still be transferable and processedin the manufacturing process. In this way, a mechanized production linein which rolls (or webs) of materials are processed into final productscan be implemented.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example in embodimentsand not limitation in the figures of the accompanying drawings in whichlike references indicate similar elements. The figures are not shown toscale unless indicated otherwise in context.

FIG. 1 illustrates a cross-section through a schematic, perspective viewof a prior art transdermal therapeutic system.

FIG. 2 illustrates a sectional view through another prior arttransdermal therapeutic system.

FIG. 3 illustrates a sectional view of a prior art system.

FIG. 4 illustrates a sectional view of a system of the presentinvention.

FIG. 5 illustrates a plan view of a barrier frame of a system of thepresent invention.

FIG. 6 illustrates an isometric perspective view of a barrier frame of asystem of the present invention.

FIG. 7 illustrates a plan view of the system of FIG. 4 of the presentinvention.

FIG. 8 illustrates a sectional view of another embodiment of a system ofthe present invention.

FIG. 9 illustrates a sectional view of yet another embodiment of asystem of the present invention.

FIG. 10 illustrates a sectional view of another embodiment of a systemof the present invention.

FIG. 11 illustrates a schematic view of a manufacturing step in anembodiment of manufacturing according to the present invention.

FIG. 12 illustrates a schematic view of a manufacturing step in anembodiment of manufacturing according to the present invention.

FIG. 13 illustrates a schematic perspective view of a manufacturing stepin an embodiment of manufacturing according to the present invention.

FIG. 14 illustrates a schematic view of a manufacturing step in anembodiment of manufacturing according to the present invention.

FIG. 15 illustrates a schematic view of a manufacturing step in anembodiment of manufacturing according to the present invention.

FIG. 16 illustrates an isometric perspective view of a partiallyfinished product in an embodiment of manufacturing process according tothe present invention.

FIG. 17 illustrates a schematic plan view of an embodiment of atransdermal drug delivery patch according to the present invention.

DETAILED DESCRIPTION

The present invention relates to delivery of one or more pharmaceuticalagents, including galantamine, through a body surface (e.g. skin)involving the use of an reservoir that incorporates the drug galantamineand optionally other ingredients such as other pharmaceutical agents andenhancers and having an adhesive layer to maintain the delivery systemon a body surface of an individual. In the present invention, a barrierlayer is used to prevent the reservoir material with drug in its matrixto come into contact with another matrix in the device.

In describing the present invention, the following terms are to be usedas indicated below. As used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referencesunless the content clearly dictates otherwise.

As used herein, the term “transdermal” refers to the use of skin,mucosa, and/or other body surfaces as a portal for the administration ofdrugs by topical application of the drug thereto for passage into thesystemic circulation. Such passage can take place through intact surface(such as skin) without wounds or punctures.

“Biologically active agent” is to be construed in its broadest sense tomean any material that is intended to produce some biological,beneficial, therapeutic, or other intended effect, such as enhancingpermeation, relief of pain, or symptoms of Alzheimer disease ordementia, etc.

As used herein, the term “drug” refers to any material that is intendedto produce some biological, beneficial, therapeutic, or other intendedeffect, such as improve symptoms of Alzheimer's disease or dementia.

As used herein, the term “therapeutically effective” refers to theamount of drug or the rate of drug administration needed to produce thedesired therapeutic result.

EMBODIMENTS

FIG. 4 shows an embodiment of the present invention. The transdermaldrug delivery device 12 includes a drug reservoir 3 disposed on abacking layer 2, and a peelable (removable) protective layer 5 (orrelease liner). Upon use, the protective layer or release liner 5 isremoved and the device is applied such that the reservoir is applied tothe body surface. The reservoir 3 is a matrix (carrier) that is suitablefor carrying the pharmaceutical agent (or drug) for transdermaldelivery. Another matrix layer (which can be an adhesive layer) 6 isdisposed more distal from the release liner 5. The matrix layer 6 can bea layer to provide adequate adhesion to a body surface to which thedevice is to be applied or to provide another agent for delivery to thebody surface, or both. Another backing layer 10 is disposed on thematrix layer 6 and being more distal from the release liner 5.

For the sake of clarity and illustration the following will refer to thematrix layer 6 as an adhesive layer. A barrier frame 14 is disposedbetween the adhesive layer 6 and the backing layer 2 of the reservoir 3.FIG. 5 shows a top plan view of the barrier frame 14 and FIG. 6 shows anisometric perspective view of the barrier frame 14. The barrier frame 14is frame shaped and has an outer perimeter 16 and an inner perimeter 18,which defines a window opening 20. FIG. 7 is a plan view looking fromthe viewpoint of the body surface at the device with the release liner 5removed for the sake of clarity in the drawing. The reservoir 3 has anouter perimeter (or edge) 22 that is between the inner perimeter 18 andouter perimeter 16 of the barrier frame 14. The width (i.e., thedistance between the inner perimeter 18 and outer perimeter 16) of thebarrier frame 14 is selected, considering the cold flow characteristicsand expected shelf life of the device, such that the barrier frame willprevent cold flow reservoir material to migrate past the outer perimeter16. As used herein, the term “between” means only that something is in aposition intermediate two other things and does not necessarily meanthat it is immediately adjacent to them or contacting them, unlessspecified to be the case.

The overlay adhesive layer 6 is larger in area and in outer perimeterthan the barrier frame 14. Thus, the overhang portion 8 outside of theframe 14 will provide adhesion to the body surface. The backing layer 10is hidden by the overlay adhesive layer 6 and is therefore not shown.The figures are not shown to scale. In fact, the thicknesses of thevarious layers are relatively thin such that the device is flexible andgenerally flat when laid on a flat surface. Therefore, when pressure isapplied to the flat surface of the device, either during manufacture orin use, the void area in the window is substantially filled so that theadhesive layer 6 attaches to the backing layer 2 within the window.

FIG. 8 illustrates another embodiment in which a transdermal drugdelivery patch 24 has layers of matrixes and barrier frames layered instep progression. Each matrix layer, whether it is a reservoir or anadhesive, has a backing layer attached to the matrix layer on the sidedistal to the skin so that the matrix side faces toward the skin. Eachmatrix layer has the same surface area and a perimeter the same as thoseof the corresponding backing layer. The patch 24 has an adhesive overlay6 attached to a backing layer 10. Most proximal to the skin is a firstreservoir layer 23 with its backing layer 26 attached on the side of thereservoir layer 23 distal from the skin. A removable release liner (notshown for the sake of clarity of the drawing but is similar to thatshown in FIG. 3 and FIG. 4) is on the reservoir side facing toward theskin. A second reservoir layer 28, with its backing layer 30, isdisposed between (although not directly attached to) the overlayadhesive 6 (with its backing layer 10) and the first reservoir layer 23(with its backing layer 26).

In FIG. 8, a first barrier frame 34 with a window opening 32 is disposedbetween and attached to the second reservoir layer 28 and the firstreservoir backing layer 26. The outer perimeter of the second matrixlayer 28 is larger than the outer perimeter of the first barrier frame34, which in turn is larger than the outer perimeter of the firstreservoir layer 23. The first barrier frame 34 has an inner perimeter,which forms the first window opening 32 that is smaller than the outerperimeter of the first reservoir 23. This way, the first barrier frame34 has a ring of exposed area 38 (i.e., not covered by the backing layer26) encircling the outer perimeters of the first reservoir layer 23 andits backing layer 26. This exposed area 38, of course, can be covered bya release liner before use, or covered by skin when in use. This exposedarea 38 will prevent the first reservoir 23 to migrate to a position tocontact the second reservoir layer 28.

The second reservoir layer 28 has a ring of exposed area 40 encirclingthe outer perimeters of the first barrier frame 34 and the firstreservoir layer 23 such that upon application to the body surface atleast a portion of the ring of exposed area 40 will contact the bodysurface for delivery of an agent from the second reservoir layer 28 tothe tissue through the body surface. The agent will migrate from themore central part of the second reservoir layer 28 to the exposed areaas the drug concentration changes upon delivery of the agent.

A second barrier frame 42 is disposed between and attached to thebacking layer 30 of the second reservoir layer 28 and the overlayadhesive layer 6. Again, the perimeters of theses layers have acascading relationship similar to the cascading relationship between thesecond reservoir layer 28, the first barrier frame 34 and the firstreservoir layer 23. The overlay adhesive layer 6 has the largest outerperimeter among the matrixes and adhesives.

FIG. 9 illustrates an embodiment in which a second drug reservoir layerwith a second drug wherein the second drug is not to be delivered duringnormal use of the device, or to be delivered only in a controlled orslowed rate. The multiple-drug device 50 has a first reservoir layer 23with its backing layer 26, a barrier frame 34, and an overlay adhesivelayer 6, with its backing layer 10, similar to those of the embodimentsof FIG. 4 and FIG. 8. However, in the device of FIG. 9, a secondreservoir layer 52, with it's backing layer 54, is disposed between theoverlay adhesive layer 6 and the first reservoir layer 23. The backinglayer 54 of the second reservoir layer 52 is attached to the overlayadhesive layer 6. The second reservoir layer 52 and it's backing layer54 are encircled by the barrier frame 34. Thus, the second reservoirlayer 52 is completely isolated within the window of the barrier frame34. This device is particularly useful for containing antagonist drug(s)in the second layer to counter the effect of a first drug in the firstreservoir layer 23. For example, if the first reservoir layer 23contains a narcotic, e.g., fentanyl, an antagonist drug, e.g.,naltrexone, can be included in the second reservoir layer. It is onlywhen the device is subject to abuse, such as extraction by fluid orphysical stress such as chewing, will the antagonist be released. Arelease liner on the first reservoir 23 is not shown for the sake ofclarity of the drawing. Instead of an antagonist, an anti-abuseunpleasant agent that is foul-tasting (e.g., bitter, hot, peppery, orother un-welcomed taste) or which can cause unpleasant sensation (e.g.,nauseating, etc.) can be placed in the second layer. For example, when aperson chews on the device or takes a solvent extract from the device,the agent would give the person a very unpleasant sensation.

A method of manufacture and construction for a system containing anoccluded counter acting agent (antagonist) as shown in FIG. 9 caninclude the following, assuming fentanyl and naltrexone-HCl are used asagonist and antagonist for illustration purposes:

Fentanyl base would be completely dissolved and mixed in a solution ofsolvent (such as ethyl acetate) and polyacrylate adhesive such asNational Starch DURO-TACK 87-4287. The solution would be formulated sothat the concentration of fentanyl would not exceed the solubility offentanyl in the polymer (about 10%) once the solvent is removed. Thesolution would be coated to a uniform thickness on a 1-5 mil (0.025mm-0.125 mm) thick silicone coated polyethylene terapthalate film (PETrelease coated liner) or similar. The liner and fentanyl polymersolution are passed through a series of ovens to remove the solventforming a dry uniform film, typically less than 5 mils (0.125 mm) thick.The dried film would then be laminated to a second non-coated PET linerfor further processing.

The antagonist layer would be produced by melting a polymer such asethylene vinyl acetate (EVA-9, EVA-22, EVA-40, etc.), ethylene octene(ENGAGE), or similar elastomeric polymer, and blending in naltrexone-HClat a concentration of 50-90%. The blend would be mixed to uniformity andextruded between two films such as PET liners, one of which would berelease coated.

The two component films would be die cut and assembled on anotherpolyisobutylene (PIB), polyacrylate, or similar adhesive (78) on aEVA/PET, polymer fiber woven, (80) or similar overlay film in aconverting operation as follows: Barrier frames (84) would be die cutfrom a 0.5-5 mil (0.0125 mm-0.125 mm) thick PET film such that the inner(18) and outer edges (16) were respectively slightly larger and smallerthan the target matrix area (23,26) and uniformly spaced on the overlayadhesive (78). The naltrexone-EVA (52) on PET film (54) would be die cutto the target size and placed on the adhesive (6) within the innerboundary of the frames (34). The release coated liner would be removedin this assembly step.

The matrix film would be cut to the appropriate length and width (23,26)and placed on top of the barrier frames (34), completely isolating thenaltrexone component (52).

If desired, an additional barrier frame can be disposed between thesecond reservoir layer and the overlay adhesive layer. This is shown inFIG. 10, which for the sake of clarity of illustration shows a matrixlayer and its corresponding backing layer as a single layer, representedby the matrix layer. In FIG. 10, a second barrier frame 58, having outerperimeter larger than the second reservoir layer 62, separates theoverlay layer 60 and the second reservoir layer 62. Based on the abovecascading design, further layers of matrixes and barriers can beincluded.

The drug (pharmaceutical agent) reservoir can be either a single phasepolymeric composition or a multiple phase polymeric composition, asdiscussed earlier. In some embodiments, more than one component, e.g., adrug and a permeation enhancer, is present, and may be in amounts abovesaturation concentration. Preferably, the whole matrix, with drugs andother optional ingredients, is a material that has the desired adhesiveproperties, in which case, the reservoir 3 is formed using apharmaceutically acceptable polymeric material that can provide adhesiveproperty for application to the body surface.

The backing layers may be formed from any material suitable for makingtransdermal delivery patches, such as a breathable or occlusive materialincluding fabric, polyvinyl acetate, polyvinylidene chloride,polyethylene, polypropylene, polyurethane, polyester, ethylene vinylacetate (EVA), polyethylene terephthalate (PET), polybutyleneterephthalate, coated paper products, aluminum sheet and the like, and acombination thereof. In preferred embodiments, the backing layerincludes low density polyethylene (LDPE) materials, medium densitypolyethylene (MDPE) materials or high density polyethylene (HDPE)materials, e.g., SARANEX (Dow Chemical, Midland, Mich.). The backinglayer may be a monolithic or a multilaminate layer. In preferredembodiments, the backing layer is a multilaminate layer includingnonlinear LDPE layer/linear LDPE layer/nonlinear LDPE layer. The backinglayer preferably has a thickness of about 0.012 mm (0.5 mil) to about0.125 mm (5 mil); more preferably 0.025 mm (1 mil) to about 0.1 mm (4mil); even more preferably 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5mil).

The purpose of the barrier frame is to separate materials, therefore theactive compounds, excipients, and polymers within the system should havenegligible solubility or permeability in the barrier material. It isdesirable for the barrier material to serve as a processing web duringassembly, thus mechanical strength (i.e. inelastic) in the web directionmay be desirable. Further, the barrier frame may be used as a separatingpoint in some system designs, therefore it may be release coated on oneor both sides of the barrier frame. Materials that can be used formaking a barrier frame include, for example, polyethylene terephthalate(PET) film, polyvinyl acetate, polyvinylidene chloride, polyethylene,polypropylene, polyurethane, polyester, polybutylene terephthalate,coated paper products, aluminum sheet and the like, and any combinationthereof. The barrier material can be used with another layer (e.g., as alaminate) of a material that is a less effective barrier without thebarrier material. The thickness of the barrier layer (e.g., barrierframe) preferably ranges between 0.012 mm (0.5 mil) and 0.125 mm (5.0mil), with or without release coating on either side. Other materialscan be used, as long as the active agent or permeation enhancers areinsoluble in them.

The reservoir or matrix may be formed from drug (or biological activeagent) reservoir materials as known in the art. For example, the drugreservoir is formed from a polymeric material in which the drug hasreasonable solubility for the drug to be delivered within the desiredrange, such as, a polyurethane, ethylene/vinyl acetate copolymer (EVA),acrylate, styrenic block copolymer, and the like. In preferredembodiments, the reservoir 3 is formed from a pharmaceuticallyacceptable pressure sensitive adhesive, preferably an acrylatecopolymer-based adhesive, as described in greater detail below.

The adhesive reservoir 3 may be formed from standard pressure sensitiveadhesives. Examples of known pressure sensitive adhesives include, butare not limited to, acrylates, polysiloxanes, polyisobutylene (PIB),polyisoprene, polybutadiene, styrenic block polymers, and the like.Examples of styrenic block copolymer-based adhesives include, but arenot limited to, styrene-isoprene-styrene block copolymer (SIS),styrene-butadiene-styrene copolymer (SBS),styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogsthereof. PIB generally has poorer solubility for drugs than acrylateadhesives. Thus, acrylate polymers are preferred as the matrix for drugreservoirs but either PIB or acrylates are preferred as an overlayadhesive layer. The drug reservoir or the matrix layer can have athickness of 0.025-0.25 mm (1-10 mils), preferably 0.05-0.12 mm (2-5mils), more preferably 0.05-0.075 mm (2-3 mils).

It is desired that the material for the matrix in the reservoir has ahigh solubility for the agent to be delivered through the body surface,either for therapeutic drug agents or permeation enhancers to facilitatethe delivery. If the reservoir material does not provide adequateadhesiveness for multiple day use, the overlay adhesive layer should bemade with an adhesive material that has stronger and sufficient adhesiveand cohesive properties for multiple day application.

Preferred materials for making the reservoir or overlay adhesive coatingaccording to the present invention include acrylates, which can be acopolymer of various monomers (“soft” monomer, “hard” monomer, and“functional” monomer) or blends of copolymers. Acrylic polymers providegood solubility for many agents. The acrylic polymers can be composed ofa copolymer or terpolymer including at least two or more exemplarycomponents selected from the group including acrylic acids, alkylacrylates, methacrylates, copolymerizable secondary monomers or monomerswith functional groups. Functional monomers are often used to eitherprovide needed functionality or improve cohesive properties throughgrafting or cross-linking. Examples of functional monomers are acids,e.g. acrylic acid, methacrylic acid and hydroxy-containing monomers suchas hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamides ormethacrylamides that contain amino group and amino alcohols with aminogroup protected. Functional groups, such as acid and hydroxyl moietiescan also help to increase the solubility of basic ingredients (e.g.,drugs) in the polymeric material. Additional useful “soft” and “hard”monomers include, but are not limited to, methoxyethyl acrylate, ethylacrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexylmethacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctylacrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexylmethacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate,dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate,hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl acetate,acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethylacrylate, dimethylaminoethyl methacrylate, tert-butylaminoethylacrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate,methoxyethyl methacrylate, and the like. Additional examples ofappropriate acrylic adhesives suitable in the practice of the inventionare described in Satas, “Acrylic Adhesives,” Handbook ofpressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989). The acrylic adhesives arecommercially available (National Starch and Chemical Corporation,Bridgewater, N.J.; Solutia, Mass.). Further examples of acrylate-basedadhesives are as follows, identified as product numbers, manufactured byNational Starch (Product Bulletin, 2000): DURO-TAK® 87-4098, 87-2287,87-4287, 87-2051, 87-2052, 87-2054, 87-2196, 87-9259, 87-9261, 87-2979,87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87-9085, 87-2525,87-2825, 87-200A, 87-201A, 87-2194, 87-2677, 87-900A, and 87-9301.DURO-TAK® 87-2287 and 87-4287 both are polymeric adhesive having similarmonomer compositions: 5.2 wt % 2-hydroxyethyl acrylate monomer, about20-40 wt % vinyl acetate, and about 55-75 wt % 2-ethylhexyl acrylate;and these two polymeric adhesives are provided solubilized in ethylacetate in solids content of about 40-50 wt %. The DURO-TAK® 87-2287adhesive is also mentioned in U.S. Pat. No. 5,693,335.

The acrylic polymers can include cross-linked and non-cross-linkedpolymers. The polymers can be cross-linked by known methods to providethe desired polymers. In some typical embodiments, the adhesive at thestage of application to the skin is a acrylate adhesive having a glasstransition temperature (T_(g)) less than −10° C., preferably −10° C. toabout −30° C., more preferably having a T_(g) of about −20° C. to about−40° C. The molecular weight of the acrylate adhesive, expressed asweight average (MW), preferably ranges from 25,000 to 10,000,000,further preferably from 50,000 to about 3,000,000 and more preferablyfrom 100,000 to 1,000,000 prior to any cross-linking reactions. Uponcross-linking the MW can further increase, as known to those involved inthe art of polymer chemistry.

As aforementioned, the reservoir(s) can include a multiple phasecomposition or a single phase polymeric composition, free of undissolvedcomponents, containing an amount of the drug sufficient to induce andmaintain the desired therapeutic effect in a human for at least threedays. The present invention has utility in connection with the deliveryof wide variety of drugs (such as those mentioned in U.S. PublicationNo. 20030026829), in addition to galantamine, delivered through bodysurfaces and membranes, including skin.

The dissolved galantamine content in the drug reservoir matrix can beabove 5 wt % on solids. However galantamine content above 10 wt % ispreferred, prefereably above 15 wt %, more preferably from 15 wt % to 35wt %, more preferably above 20 wt %, even more preferably from 20 wt %to 30 wt %. Such galantamine contents are suitable for effecting flux oftherapeutic effect for ailments such as Alzheimer's disease or dementia,with a flux of, e.g., greater than 10 μg/cm²-hr, preferably about 12.5to 18.8 μg/cm²-hr for a 3 day patch, more preferably a 7 day patch. Itis noted that galantamine base, salts or esters thereof, or analogsthereof, as known by those skilled in the art, can also be deliveredwith devices of the present invention having barrier(s), since theadvantage of having the barrier in a device is not limited togalantamine base alone. The galantamine can be in any reservoir that hasa flow path for the galantamine to migrate to a body surface of the userindividual. As used herein, when the term “galantamine” is used, it canmean galantamine base, salt, ester, or analog unless specified to beotherwise in the content.

As indicated in the above, in some embodiments, the reservoir or theadhesive may contain additional components such as, additives,permeation enhancers, stabilizers, dyes, diluents, plasticizer,tackifying agent, pigments, carriers, inert fillers, antioxidants,excipients, gelling agents, anti-irritants, vasoconstrictors and othermaterials as are generally known to the transdermal art. Typically, suchmaterials are present below saturation concentration in the reservoir.

The protective layer (or release liner) can be made of a polymericmaterial that may be optionally metallized. Examples of the polymericmaterials include polyurethane, polyvinyl acetate, polyvinylidenechloride, polypropylene, polycarbonate, polystyrene, polyethylene,polyethylene terephthalate, polybutylene terephthalate, paper, and thelike, and a combination thereof. In preferred embodiments, theprotective layer includes a siliconized polyester sheet.

As mentioned, many adhesives are useful polymeric materials for formingdrug-containing pressure sensitive adhesive (PSA). One preferredadhesive for galantamine is polyacrylate (acrylate polymers). Afterformulating into a transdermal system with drugs, permeation enhancers,and the like, which produce plasticizing effect as well as tackifyingeffect, adhesive polymers (such as polyacrylates) plasticized withpermeation enhancers and drug would have storage modulus and creepcompliance ranges that can be used with the systems of the presentinvention. For example, the plasticized material could have a resultingcreep compliance that is about 1×10⁻³ cm²/dyn or less, preferably morethan about 7×10⁻⁵ cm²/dyn, preferably from about 7×10⁻⁵ cm²/dyn to6×10⁻⁴ cm²/dyn, more preferably about 1×10⁻⁴ cm²/dyn to 6×10⁻⁴ cm²/dyn.The preferred storage modulus of the plasticized acrylate polymer isabout 1×10^(5 dyn/cm) ² to 8×10⁵ dyn/cm², preferably about 1.2×10⁵dyn/cm² to 6×10⁵ dyn/cm², more preferably about 1.4×10⁵ dyn/cm² to 5×10⁵dyn/cm². However, even with stiff adhesives, after incorporating highdrug content, it is beneficial to have barrier layers to preventpossible flow of drug reservoir material into other adhesive layers.Contact between different matrix and adhesive layers results in drugdiffusion between such layers, resulting in undesirable changes over aprolonged period.

For rheology parameters, modulus G′ is storage modulus measured at 25°C. and 1 rad/s frequency (Frequency sweep experiment was conducted usingAR-2000 rheometer from TA Instruments (TA Instruments, 109 Lukens Drive,New Castle, Del. 19720). The test conditions are: strain 1%, temperature25° C., frequency range 0.1 to 100 rad/s, gap around 1000 micron). Creepcompliance tests are conducted using AR-2000 r heometer from TAInstruments. The test conditions are: stress 1000 dyn/cm², temperature30° C., time 3600 seconds, gap around 1000 microns, as would beunderstood by those skilled in the art.

Less stiff polymer adhesives can also be used, but such adhesives wouldhave a higher tendency to cold flow, for example, adhesives afterincorporation of ingredients (such as galantamine and permeationenhancers) with creep compliance of from greater than about 1×10⁻³cm²/dyn, as well as those with storage modulus of less than about 1×10⁵dyn/cm². The implementation of barrier films according to the presentinvention protects against undesired mixing of adhesives from differentlayers.

One can select the ingredients and the appropriate amounts thereof toresult in an effective transdermal drug delivery system with the rightadhesive properties for the desirable length of time, such as 24 hours,3 day, or even 7 day application on a body surface. When the drugreservoir tends to be a little soft due to the presence of a largeamount of drug or enhancer, the barrier frames of the present inventionis useful for preventing drug reservoir material from cold-flowing toundesirable positions.

Permeation enhancers can be useful for increasing the skin permeabilityof the drug galantamine or drug combinations to achieve delivery attherapeutically effective rates. Such permeation enhancers can beapplied the skin by pretreatment or currently with the drug, forexample, by incorporation in the reservoir. A permeation enhancer shouldhave the ability to enhance the permeability of the skin for one, ormore drugs or other biologically active agents. A useful permeationenhancer would enhance permeability of the desired drug or biologicallyactive agent at a rate adequate for therapeutic level from a reasonablysized patch (e.g., about 20 to 80 cm²). Some useful permeation enhancersinclude non-ionic surfactant, one or more can be selected from the groupincluding glyceryl mono-oleate, glyceryl mono-laurate, sorbitanmono-oleate, glyceryl tri-oleate, and isopropyl myristate. The non-ionicsurfactant can be used in the amount of 0.1 about 20 wt % solids to thetotal composition of the matrix layer. Examples of permeation enhancersinclude, but are not limited to, fatty acid esters of alcohols,including fatty acid esters of glycerin, such as capric, caprylic,dodecyl, oleic acids; fatty acid esters of isosorbide, sucrose,polyethylene glycol; caproyl lactylic acid; laureth-2; laureth-2acetate; laureth-2 benzoate; laureth-3 carboxylic acid; laureth-4;laureth-5 carboxylic acid; oleth-2; glyceryl pyroglutamate oleate;glyceryl oleate; N-lauroyl sarcosine; N-myristoyl sarcosine;N-octyl-2-pyrrolidone; lauraminopropionic acid; polypropyleneglycol-4-laureth-2; polypropylene glycol-4-laureth-5dimethy-1 lauramide;lauramide diethanolamine (DEA). Preferred enhancers include, but are notlimited to, pyroglutamate (such as octyl-, ethyl-, lauryl pyroglutamate(LP)), glyceryl monolaurate (GML), glyceryl monocaprylate, glycerylmonocaprate, glyceryl monooleate (GMO) and sorbitan monolaurate. Otherpermeation enhancers that could improve drug permeability include:isosorbide, oleth-4, ethoxydiglycol, and lauryl pyrrolidone. Additionalexamples of suitable permeation enhancers are described, for example, inU.S. Pat. Nos. 5,785,991; 5,843,468; 5,882,676; and 6,004,578. As usedherein, “permeation enhancers” is meant to include dissolutionassistants, unless specified otherwise in context.

As already mentioned, the formulations can contain various types ofenhancers. One type is acidic, including, e.g., fatty acids, e.g., oleicacid, linoleic acid, linolenic acid, arachidonic acid, lauric acid,myristic acid serve as solubilizers for the polar galantamine,increasing the concentration of drug that can be loaded into theadhesive. A second type of useful enhancers are fatty acid esters,alcohol, or fatty acid/base reaction products, such as isopropylmyristate (a fatty ester), lauryl pyrrolidone (amide), laureth-2 (fattyalcohol ether), glycerol monooleate (fatty acid ester), lauryl lactate(fatter acid ester), 1,2-dihydroxydodecane (fatty alcohol), ethylpalmitate (fatty ester). These can also serve as cosolvents forgalantamine in skin, enabling high flux. Other than the above, annonexhaustive list of useful permeation enhancers that enable high fluxrate include selachyl alcohol, laureth-4 (fatty alcohol ether), oleth-2(fatty alcohol ether), and N-lauroyl sarcosine (fatty acid).

In some embodiments, a large amount of permeation enhancer may be neededto aid the drug in transdermal delivery. The present invention isespecially suitable for such transdermal delivery systems. Permeationenhancers in the polymer composition can be 10 wt % or high, 15 wt % andhigher, greater than 20 wt %, or even greater than 30 dry weight % (orsolids wt %). The permeation enhancers and the galantamine canconstitute more than 25 wt % of the matrix reservoir, preferably morethan 30 wt %, more preferably about 30 wt % to 50 wt %, in someembodiments even about 40 wt % to 50 wt % of the matrix reservoir.

In certain embodiments, polyvinylpyrrolidone (PVP) can be incorporatedinto the acrylate polymer matrix to increase cohesive strength and toaffect the adhesive properties of the galantamine transdermal system.The incorporation of PVP resulted in an increase in modulus and decreasein creep compliance. PVP works particularly well with acrylate polymeradhesives that contain hydroxyl or acid functionalities, or both. Bothof these functionalities have the capability to interact with PVP. Morethan 5 wt %, preferably from 5 wt % to 20 wt % of PVP on matrix solidscan be used to increase modulus, decrease creep compliance, and improvethe adhesive properties of the transdermal formulation without reducinggalantamine solubility significantly.

As aforementioned, the drug reservoir contains galantamine, preferablytotally dissolved in the matrix of the reservoir, or present as acrystalline dispersion in the reservoir. It is understood that thereservoir can also contain other drugs, preferably in a single phasepolymeric composition. Other drugs that can be contained in the drugreservoir include, for example, those disclosed in U.S. Pat. No.6,004,578. One skilled in the art will be able to incorporate such drugsbased on the disclosure of the present invention.

A wide variety of materials that can be used for fabricating the variouslayers of the drug delivery patches according to this invention havebeen described above. This invention therefore contemplates the use ofmaterials other than those specifically disclosed herein, includingthose which may hereafter become known to the art to be capable ofperforming the necessary functions.

Transdermal flux can be measured with a standard procedure using Franzcells or using an array of formulations. Flux experiments were done onisolated human cadaver epidermis. With Franz cells, in each Franzdiffusion cell a disc of epidermis is placed on the receptorcompartment. A transdermal delivery system is placed over the diffusionarea (1.98 cm²) in the center of the receptor. The donor compartment isthen added and clamped to the assembly. At time 0, receptor mediumsolution (between 21 and 24 ml, exactly measured) is added into thereceptor compartment and the cell maintained at 35° C. This temperatureyields a skin surface temperature of 30-32° C. Samples of the receptorcompartment are taken periodically to determine the skin flux andanalyzed by HPLC. In testing flux with an array of transdermal miniaturepatches, formulations are prepared by mixing stock solutions of each ofthe mixture components of formulation in organic solvents (about 15 wt %solids), followed by a mixing process. The mixtures are then aliquotedonto arrays as 4-mm diameter drops and allowed to dry, leaving behindsolid samples or “dots.” (i.e., mini-patches). The miniature patches inthe arrays are then tested individually for skin flux using a permeationarray, whose principle of drug flux from a formulation patch throughepidermis to a compartment of receptor medium is similar to that ofFranz cells (an array of miniature cells). The test array has aplurality of cells, a piece of isolated human epidermis large enough tocover the whole array, and a multiple well plate with wells acting asthe receptor compartments filled with receptor medium. The assembledpermeation arrays are stored at 32° C. and 60% relative humidity for theduration of the permeation experiments. Receptor fluid is auto-sampledfrom each of the permeation wells at regular intervals and then measuredby HPLC for flux of the drug.

Administration of the Drug

On application to the skin, the drug in the drug reservoir of thetransdermal patch diffuses into the skin where it is absorbed into thebloodstream to produce a systemic therapeutic effect. The onset of thetherapeutic depends on various factors, such as, potency of the drug,the solubility and diffusivity of the drug in the skin, thickness of theskin, concentration of the drug within the skin application site,concentration of the drug in the drug reservoir, and the like.Typically, it is preferable that a patient experiences an adequateeffect within a few hours (e.g., 3-6 hours) of initial application.However, this is significant only on the initial application. Onrepeated sequential application, the residual drug in the applicationsite of the patch is absorbed by the body at approximately the same rateas the drug from the new patch is absorbed into the new applicationarea. Thus the patient should not experience any interruption of thetherapeutic effect, such as analgesia.

When continuous therapeutic effect is desired the depleted patch wouldbe removed and a fresh patch is applied to a new location. For example,the patch would be sequentially removed and replaced with a fresh patchat the end of the administration period to provide continual therapeuticeffect. Since absorption of the drug from the fresh patch into the newapplication area usually occurs at substantially the same rate asabsorption by the body of the residual drug within the previousapplication site of the patch, blood levels will remain substantiallyconstant. Additionally, it is contemplated that doses may be increasedover time and that concurrent use of other drugs may occur to deal witha need for increased relief.

Methods of Manufacture

The transdermal devices are made from laminates which are manufacturedaccording to known methodology. In general, in an embodiment, a solutionof the polymeric reservoir material, as described above, is added to amixer, with the desired amounts of the drug, permeation enhancers, andother ingredients that may be needed. Preferably, the polymericreservoir material is an acrylate material to provide adhesive propertyto the transdermal delivery device. Typically, the acrylate material issolubilized in an organic solvent, e.g., ethanol, ethyl acetate, hexane,and the like. The mixer is then activated for a period of time toachieve acceptable uniformity of the ingredients. The mixer is attachedby means of connectors to a suitable casting die located at one end of acasting/film drying line. The mixer is pressurized using nitrogen tofeed solution to the casting die. Optionally the solution is transferredto a pressurizable tank. Solution is cast as a wet film onto a movingsiliconized polyester web. The web is drawn through a series of ovens toevaporate the casting solvent to acceptable residual limits. The driedreservoir film is then laminated to a selected backing membrane and thelaminate is wound into rolls. However, the materials may also be dryblended and extruded to produce a similar laminate. In subsequentoperations, the laminate is further processes in conjunction with otherlaminate(s) to result in individual patches that are die-cut, separatedand unit-packaged using suitable pouchstock. Laminates of otherreservoir materials can be made by people skilled in the art.

The present invention is particularly adapted for mass manufacturingpractices using mechanized automated machineries. In such manufacturepractices, long rolls (can be considered to be long strips) or webs oflaminate materials are fed through roller nips for further lamination tocomplete the assembly and dies for cutting and alignment. For practicalmechanical handling, such webs can be considered to be continuous. Thus,a reservoir, or matrix material needs to have a backing or some kind offlexible but strong (tough and not easily torn) material attached to itfor ease of transfer. In this way, rolls of materials can be processedwithout tearing.

FIGS. 11 to 14 illustrate how mass production by machines involvingrepetitive mechanical die-cutting and pressing processes are used tomake exemplary patches such as those of FIG. 4. The repetitivemechanical die-cutting is done in cycles of motion as in most computeror process-controlled machines. In this embodiment of the method, thedies are rotary dies. Cut pieces can be picked up by suction (orvacuum). Left over scrap material (which may have a ladder shape whencenter pieces are taken out) is pulled into an uptake.

Typically, the manufacture of a product of an embodiment similar to thatshown in FIG. 4 involves two laminates. The drug/adhesive matrix islocated between a PET film and a release liner in a laminate. Theoverlay laminate has another adhesive layer between a backing and arelease liner. A PET film is used for the barrier layer also. Fourpayouts will be required, one for each laminate, one for the PET barrierfilm, and one for the final release liner. In this embodiment, sixtake-ups are used, one for the temporary liner from the overlaylaminate, one for the barrier frame scrap, one for the drug laminateedge trim, one for the temporary liner from the drug/matrix laminate,one for the overlay scrap, and one for the final die-cut product. Fourdies are used to produce the finished assembly as follows.

FIG. 11 shows a schematic view of how a rotary vacuum die 72 in which aPET film 70 payout (payout #1) is fed into a die station 72 where asquare or rounded barrier “frame” similar to that shown in FIG. 5 andFIG. 6 is cut, carried, and placed in a registered position onto theadhesive side of an overlay laminate. The barrier frames are not shownin FIG. 11 as they are carried around the die by vacuum. The left overscrap 74 is taken away from the die 72 by take up #1.

An adhesive laminate (which includes siliconized PET temporary linerprotecting an adhesive on a backing layer) is paid out from payout #2and the temporary release liner is stripped to result in just acontinuous strip of adhesive on a backing. The scrap release liner isremoved by take up #2 (not shown). FIG. 12 shows the web 76 of theadhesive having an adhesive layer 78 on a backing layer 80 being fed toa rotary die 82 that applies the barrier frames 84 on the adhesive sideof the strip 76, as shown by FIG. 13, forming a web of adhesive overlays86. The window in a barrier frame 84 advantageously allows the adhesivematerial of the adhesive layer 78 to later attach to the backing of acut discrete unit of the reservoir layer, thus, facilitating themechanized transferring and application of the reservoir layer.

As shown in FIG. 14, a continuous strip 88 of drug/adhesive matrix(reservoir) is paid out (payout #3) to a rotary slitting die 90 to beslit and spread by a spreader 92 to the appropriate width so that theslit strips 94 can be spread and aligned to the adhesive overlay layer86, which can be made of, e.g., PIB. The edges of the continuous strip88 are also trimmed to result in a suitable width that facilitatesforming the adhesive units that correspond to the barrier frames later.The edge trim is cut and removed (take-up #3, which is not shown in FIG.14).

FIG. 15 shows how the system web is combined with the slit strip 94adhesive web. The system die 96 cuts the slit web 94 to discrete systemunits of drug reservoir and backing of the desired length. The discretesystem units are lifted from the temporary liner on which they werecarried. Leftover temporary liner (not shown in the diagram) is carriedoff as take up #4. The discrete units 101 of system reservoir/backingare then spaced, transferred, and laminated to the final liner 100 frompayout #4 (not shown).

A lamination roller 98 applies the drug reservoir units on the finalliner 100 to the adhesive overlay 86. The system webs (i.e., the webswith the drug reservoir) and overlay web are joined such that the systemedges fall within the center of the “frames” on the overlay. Since thebarrier frames 84 are discrete units spaced apart on the adhesiveoverlay 86 the slit strip 94 has to similarly space the drug reservoirson the final liner 100 from payout #4. This is accomplished by havingonly intermittent contact between the slit strip and the final liner atdie 96. The final liner web is accelerated when not in contact with thedie 96, and decelerated to match the die speed for the duration of thecontact, creating the spacing. This results in a web 102 with discreteunits 103 of drug reservoirs 3 attached to backing layers 2 and barrierframes 84, which are shown in FIG. 15 and FIG. 16. The web 102 is thenkiss cut by die 104 through the overlay adhesive to define the overlaydimensions and the excess adhesive is removed (take up #5). Theresulting strip 106 is collected (take-up #6), and can then be cut, fedbetween two strips of protective material, sealed, and cut intoindividual pouches containing the devices.

The patches can be made such that only one reservoir matrix island in ona patch, similar to the patch of FIG. 4. However, the transdermal drugdelivery systems (patches) can be cut in such a way that two or moreislands of reservoir matrix can be present on a single patch, as shownin FIG. 17 (showing an example of two islands), which can be made if theconfiguration of FIG. 16 is cut to include multiple islands. Between theislands is a space allowing the adhesive from the overlay to showthrough to aid adhesion to the skin. When such a patch is applied to anindividual, the area between the active matrixes would provideadditional adhesion maximizing skin contact and therefore flux. Thisdesign increases average skin contact for extended wear of large highlyloaded adhesives, in which adhesion usually decreases as the componentsleave the system and or moisture is absorbed.

EXAMPLES

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.Modulus G′ was storage modulus at 25° C. and 1 rad/s frequency(Frequency sweep experiment was conducted using AR-2000 rheometer fromTA Instruments (TA Instruments, 109 Lukens Drive, New Castle, Del.19720). The test conditions were: strain 1%, temperature 25° C.,frequency range 0.1 to 100 rad/s, gap around 1000 micron). Creepcompliance tests were conducted using AR-2000 rheometer from TAInstruments. The test conditions were: stress 1000 dyn/cm², temperature30° C., time 3600 seconds, gap around 1000 microns, as would beunderstood by those skilled in the art. In the following examples,galantamine base is used, although it is understood that salts, esters,and analog may also be used in similar fashion by one skilled in theart.

Example 1 Barrier Frame Application, in which Active PharmaceuticalIngredient is Galantamine

A galantamine-containing polyacrylate adhesive solution is mixed withflux enhancing agents such as lauryl pyrollidone, oleic acid, lauryllactate. The adhesive is a National Starch DURO-TAK® 87-4287 adhesivewhich is a polymerization product of vinyl acetate, 2-ethylhexylacrylate, and hydroxyethyl acrylate. The solution is film cast toapproximately 9 mils (0.225 mm) thick on a 2 mil (0.05 mm) or 3 mil(0.075 mm) siliconized polyethelene terepathalate (Si-PET) film (alsoknown as release liner) and dried according to conventional technology.Once the solvents are removed, the resulting film is approximately 5mils (0.125 mm) thick and has approximately 14 wt % galantamine. Theadhesive film is then laminated to the PET side of a 2 mil PET/EVA(ethylene vinyl acetate) backing film. The drug adhesive is referred toas a matrix.

A PIB adhesive film is prepared separately in similar fashion by mixing2 grades of poly isobutylene, with polybutene, and crospovidone inheptane. The solution is film cast at approximately 6 mils (0.15 mm)onto a 3 mil (0.075 mm) Si-PET (silicone coated PET) film, dried to 3mils (0.075 mm) as above, and laminated to a polyester interlock fabric.

Both the drug matrix film and the PIB adhesive films are simultaneouslymounted on a web converting machine along with an uncoated 1-2 mil(0.025 mm-0.05 mm) PET film from which the barrier frames are cut and a3 mil (0.075 mm) Si-PET film which will be used as the final systemliner.

The following steps describe the order of assembly of an individualsystem. However, all steps occur continuously in various locationsthroughout the machine in a web converting process. The individualproduct system assembled in this example has an active area of 48 cm²,centered on a barrier frame, centered on a PIB adhesive of 60 cm² allcovered by a release liner.

-   -   1. The release liner is peeled (stripped) from the PIB adhesive        laminate.    -   2. The uncoated PET film is fed through a rotary die, cutting        both the inner and outer perimeter of the frame to the desired        dimensions. The frame outer perimeter and inner perimeter        dimensions are approximately ±0.1 inches (2.54 mm) of the        perimeter of the active area (i.e., the drug reservoir area) of        the finished product.    -   3. The frame and center are carried by vacuum around the rotary        die where the center piece is blown off and removed by a second        vacuum.    -   4. The remaining frame is transferred to the adhesive surface of        the PIB film of step 1.    -   5. The drug matrix is slit and spread to align with the frames        on the PIB web.    -   6. The drug matrix webs are passed through a rotary die where        systems are kiss cut (cuts through the backing and drug matrix,        but not the liner) and singulated from the web and carried by        vacuum around the rotary die where the system is placed on the        final liner at a spacing consistent with the barrier frames on        the overlay adhesive.    -   7. The system web is laminated to the PIB web with the systems        placed on the centers of the frames.    -   8. A final system die cuts the PIB backing and removes the        excess overlay adhesive.    -   9. The product web is collected and is then ready for packaging.

Example 2 A Transdermal Galantamine System with Galantamine MatrixIslands

The individual product system assembled in this example has two activeareas (islands) of 20 cm², centered on barrier frames, evenly spaced ona PIB adhesive of 60 cm², all covered by a release liner.

A transdermal galantamine system is to be made through a constructionshowed in FIGS. 16 and 17. Multiple frames and matrixes with galantaminewould be assembled on a single system applicable to a patient, forexample, having a configuration like that of FIGS. 16 and 17. Thisdesign increases average skin contact for extended wear of large highlyloaded adhesives, in which adhesion usually decreases as the componentsleave the system and or moisture is absorbed. The area between theactive matrixes would provide additional adhesion maximizing skincontact and therefore flux.

Galantamine is mixed into solution of solvent (ethyl acetate) andpolyacrylate adhesive such as National Starch DURO-TAK 87-4287 withpermeation enhancers. The solution is formulated so that theconcentration of galantamine is about 5 wt % and does not exceed itssolubility in the polymer once the solvent is removed. The solution iscoated to a uniform thickness on a 5 mil (0.125 mm) thick siliconecoated polyethylene terephthalate film (PET release coated liner) orsimilar. The liner and galantamine polymer solution are passed through aseries of ovens to remove the solvent forming a dry uniform film, toless than 5 mil (0.125 mm) thick. The dried film is then laminated to asecond non-coated PET liner for further processing. The active componentfilm is die cut and assembled on another polyisobutylene (PIB) adhesive(although other adhesives, e.g., polyacrylate, or similar adhesive canbe used) (78) on a EVA/PET overlay film (80) in a converting operationas follows:

Barrier frames (84) is die cut from a 1 mil (0.025 mm) thick PET filmsuch that the inner (18) and outer edges (16) are 0.15 cm larger andsmaller than the target matrix area (3) and spaced according to adhesionrequirements on the overlay adhesive (78) 5.15 cm apart in this example.

The matrix film is cut to the appropriate length and width 4.5×4.5 cmand placed on top of the barrier frames (84). The matrix layer releasecoated liner is removed in this assembly step and replaced with a largerfinal system release liner (not shown in the figure), covering all thesystem components. The assembled system is then die cut to theappropriate size with two separate skin-contacting reservoirs on asingle patch applicable to a patient.

Example 3 A Transdermal Galantamine System with High Galantamine Loadingand Enhancers

Galantamine is mixed into solution of solvent (ethyl acetate) andpolyacrylate adhesive such as National Starch DURO-TAK 87-4287 withpermeation enhancers. The solution is formulated so that theconcentration of galantamine is about 24 wt % and above 10 wt %permeation enhancers.

The solution is coated to a uniform thickness on a 5 mil (0.125 mm)thick silicone coated polyethylene terephthalate film (PET releasecoated liner) or similar. The liner and galantamine polymer solution arepassed through a series of ovens to remove the solvent forming a dryuniform film, to less than 5 mil (0.125 mm) thick. The dried film isthen laminated to a second non-coated PET liner for further processing.The active component film is die cut and assembled on anotherpolyisobutylene (PIB) adhesive (although other adhesives, e.g.,polyacrylate, or similar adhesive can be used) (78) on an EVA/PEToverlay film (80) in a converting operation as follows:

Barrier frames (84) is die cut from a 1 mil (0.025 mm) thick PET filmsuch that the inner (18) and outer edges (16) are slightly larger andsmaller than the target matrix area (3) and spaced according to adhesionrequirements on the overlay adhesive (78).

The matrix film is cut to the appropriate length and width 4.5×4.5 cmand placed on top of the barrier frames (84). The matrix layer releasecoated liner is removed in this assembly step and replaced with a largerfinal system release liner (not shown in the figure), covering all thesystem components. The assembled system is then die cut to theappropriate size with one skin-contacting reservoirs on a single patchapplicable to a patient.

Example 4 Transdermal Galantamine Systems with High Galantamine Loadingand Enhancers

Table 1 as follows shows the storage modulus and creep compliance valuesof a number of compositions with galantamine contents of 20 wt % andabove with permeation enhancers. The percentages are the amount of thespecific respective ingredients in the composition. The balance is theadhesive in the formulation. For example, the first sample had 20 wt %galantamine, the balance (i.e., 80 wt %) was adhesive A. The storagemodulus and creep compliance values indicated that such compositionswould tend to cold flow over a period of storage time, for example,several weeks. TABLE 1 Modulus and Creep Compliance Creep Modulus G′Compliance Sample (composition) (dyn/cm²) (cm²/dyn) Adhesive A_20% Gal5.22 × 10⁵ 1.88 × 10⁻⁴ Adhesive A_20% Gal_6% OA_12% LPY 5.64 × 10⁴ 2.22× 10⁻³ Adhesive A_20% Gal_9% OA_9% LPY 5.00 × 10⁴ 2.99 × 10⁻³ AdhesiveA_22% Gal_10% OA 1.85 × 10⁵ 7.59 × 10⁻⁴ Adhesive A_25% Gal_15% LrA 1.38× 10⁵ 1.01 × 10⁻³ Adhesive A_25% Gal_12% LrA_6% IPM 6.68 × 10⁴ 2.75 ×10⁻³ Adhesive A_10% PVP_25% Gal_15% LrA 4.05 × 10⁵ 3.90 × 10⁻⁴ AdhesiveA_26% Gal_12% LrA_4% LAU 8.45 × 10⁴ 2.05 × 10⁻³ Adhesive A_26% Gal_10%LrA_3% 7.12 × 10⁴ 2.12 × 10⁻³ IPM_3% LAU Adhesive A_26% Gal_5% OA_8%6.79 × 10⁴ 2.42 × 10⁻³ LrA_5% LPY Adhesive A_30% Gal_15% LrA 1.08 × 10⁵1.60 × 10⁻³ Adhesive A_10% PVP_22% Gal_8% 2.26 × 10⁵ 7.74 × 10⁻⁴ LrA_5%LAU_5% GMO Adhesive B_20% Gal_9% OA_9% LPY 3.69 × 10⁵ 1.66 × 10⁻⁴

In Table 1, Adhesive A is a polyacrylate adhesive with monomercomponents including about 3% acrylic acid, and 30% hydroxyethylacrylate. Adhesvie B is a noncross-linked polyacrylate adhesive withmonomer components of 59% butyl acrylate, 6% acrylic acid, 9.5% t-OA(N-t-pctylacrylamide), and 25.5% hydroxyethyl acrylate. GAL isgalantamine. For the permeation enhancers, GMO is glycerol monooleate;IPM is isopropyl myristate; LAU is Laureth-2; LPY is lauryl pyrrolidone;LrA is lauric acid; OA is oleic acid; and PVP is polyvinyl pyrrolidone.

Casting solutions with solids content of the compositions of Table 1were made into using ethyl acetate as solvent. A small amount ofmethanol may also be used in addition to ethyl acetate to help solublizethe solids in the casting solution.

The casting solutions are used for casting and making patches with themethod similar to that in Example 1 and Example 3. The barrier layerwould prevent the migration of adhesive with galantamine to migrate toan adhesive near by.

The present invention has utility in connection with the delivery ofgalantamine or analogs or derivatives thereof through body surfaces andmembranes, including skin. Galantamine derivatives and analogs are knownin the art. It is noted that galantamine equivalents (analogs andderivatives), including salts and esters, can be incorporated into thedevice with or in place of galantamine base. Galantamine derivative andanalogs have been disclosed in for example, the following, U.S. Pat.Nos. 5,958,903; 6,018,043; 6,093,815; 6,184,004; 6,316,439; 6,323,195;6,323,196; US Publication 20050065338, and European Patent ApplicationNo. EP1458724A, which are incorporated by reference in their entiretiesherein.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods used by those in pharmaceutical productdevelopment within the knowledge of those skilled in the art.Embodiments of the present invention have been described withspecificity. The embodiments are intended to be illustrative in allrespects, rather than restrictive, of the present invention. It is to beunderstood that various combinations and permutations of various partsand components of the schemes disclosed herein can be implemented by oneskilled in the art without departing from the scope of the presentinvention. All U.S. patents and U.S. patent publications cited hereinare incorporated by reference herein in their entireties.

1. A device for administration of galantamine to an individual at atherapeutically effective rate through a body surface, comprising: a.reservoir having a first matrix including galantamine in a first matrix,the reservoir having a reservoir outer perimeter; b. first backing layerattached to the reservoir and substantially impermeable to galantamine;c. layer of second matrix (second matrix layer) permeable togalantamine; and d. barrier layer disposed between the reservoir and atleast part of the second matrix layer, the barrier layer having abarrier layer outer perimeter, the reservoir outer perimeter beingsmaller than the barrier layer outer perimeter, the barrier layer beingof a material that is substantially impermeable to galantamine.
 2. Thedevice of claim 1 wherein the barrier layer has a window through whichat least one of a matrix and the first backing layer can extend toattach to the other and galantamine is above 10 wt % in the reservoir.3. The device of claim 1 wherein the barrier layer has a window throughwhich at least one of a matrix and the first backing layer can extend toattach to the other and wherein the second matrix is an adhesive,wherein the reservoir and the first backing layer have flush edges andat least one of the first backing layer edges have material from thefirst matrix adhering thereto.
 4. The device of claim 3 furthercomprising a second backing layer attached to the second matrix layerand is positioned more distal from the reservoir, the second backinglayer having a second backing layer outer perimeter, the second matrixlayer having a second matrix layer outer perimeter, the second matrixlayer outer perimeter being larger than the barrier layer outerperimeter, and wherein the first backing layer has a first backing layerouter perimeter smaller than the second backing layer outer perimeter.5. The device of claim 2 wherein the second matrix layer is a layer ofadhesive that can adhere to the body surface maintaining the devicethereon for 2 days or more and wherein the second matrix is the matrixthat attaches to the first backing layer.
 6. The device of claim 1wherein the first matrix comprising an acrylate polymer in whichgalantamine is soluble and galantamine is from 15 wt % to 35 wt % in thereservoir.
 7. The device of claim 1 further comprises a second backinglayer attached to the second matrix layer and is positioned more distalto the reservoir and wherein the second matrix is an adhesive that canadhere to the body surface maintaining the device thereon for 2 days ormore.
 8. The device of claim 1 wherein the reservoir and the firstbacking layer have flush edges and at least one of the first backinglayer edges have material from first matrix adhering thereto.
 9. Thedevice of claim 1 wherein the device has an intended shelf life and thereservoir would cold flow during the shelf life such that the reservoirouter perimeter enlarges during the shelf life but does not exceed thebarrier layer outer perimeter.
 10. The device of claim 4 furthercomprising one or more permeation enhancers and galantamine is from 15wt % to 35 wt % in the reservoir and the one or more permeationenhancers and galantamine constitute more than 30 wt % in the reservoir.11. The device of claim 4 further comprising a third matrix layerattached to a third backing layer, the third backing layer having athird backing layer outer perimeter, the third matrix layer having athird matrix layer outer perimeter the same size as the third backinglayer outer perimeter but smaller than the window of the barrier layer,the third matrix layer being disposed intermediate the reservoir and thesecond matrix layer and extending in the window to attach to the firstbacking layer wherein the third matrix layer contains a non-galantaminedrug.
 12. The device of claim 4 wherein the device is made by mechanizedmass production.
 13. A device for administration of galantamine to anindividual at a therapeutically effective rate through a body surface,comprising: a. reservoir having a first matrix having a reservoir outerperimeter; including galantamine from 15 wt % to 35 wt % and permeationenhancer material of more than 10 wt % in the first matrix; b. firstbacking layer attached to the reservoir and substantially impermeable togalantamine, having a first backing layer outer perimeter, the reservoirand the first backing layer have flush edges and at least one of thefirst backing layer edges have material from the first matrix adheringthereto; c. layer of adhesive second matrix (second matrix layer)permeable to galantamine, having a second matrix layer outer perimeter;d. second backing layer attached to the second matrix layer, having asecond backing layer outer perimeter; and e. barrier layer disposedintermediate the reservoir and at least part of the second matrix layer,the barrier layer being of a material that is substantially impermeableto galantamine, the barrier layer having a window through which thesecond matrix layer and the first backing layer can adhere together atleast in portion, the second backing layer outer perimeter being thesame size as the second matrix layer outer perimeter and larger than thebarrier layer outer perimeter, the first backing layer outer perimeterbeing the same size as the reservoir outer perimeter and smaller thanthe barrier layer outer perimeter.
 14. A method of making a device fordelivery of galantamine to an individual through a body surface,comprising: a. cutting a reservoir layer and a first backing layer froma first web, the reservoir layer having a first matrix includinggalantamine in the first matrix, the first backing layer beingsubstantially impermeable to galantamine, the reservoir layer beingattached to the first backing layer and has a reservoir layer outerperimeter; and b. adhesively affixing a barrier layer intermediate thereservoir layer and at least part of a second matrix layer on a secondweb, the second matrix layer being permeable to galantamine, the barrierlayer being of a material that is substantially impermeable togalantamine, the barrier layer having a barrier outer perimeter, thereservoir layer outer perimeter being smaller than the barrier layerouter perimeter.
 15. The method of claim 14 comprising cutting a windowin the barrier layer, and affixing the barrier layer such that at leastone of a matrix and the first backing layer can extend through thewindow to attach to the other, the first backing layer being disposedintermediate the second matrix layer and the reservoir layer, andgalantamine is above 10 wt % in the reservoir layer.
 16. The method ofclaim 15 further comprising cutting from a second web the second matrixlayer attached to a second backing layer, the second backing layerhaving a second backing layer outer perimeter, the second matrix layerhaving a second matrix layer outer perimeter, such that the secondmatrix layer outer perimeter is larger than the barrier layer outerperimeter, and cutting the first web such that the first backing layerhas a first backing layer outer perimeter that is smaller than thesecond backing layer outer perimeter, and galantamine is above 15 wt %in the reservoir layer.
 17. The method of claim 15 further comprisingfeeding into a die system a web of reservoir layer material and firstbacking layer material and feeding into the die system a web of thesecond matrix layer material with the second backing material atdifferent speed, cutting the web of reservoir layer material intodiscrete reservoir layers, and attaching the discrete reservoir layerson the web of second matrix layer material such that the discretereservoir layers are spaced apart on the web of second matrix layermaterial.
 18. The method of claim 15 wherein the first web and thesecond web are mechanically cut by a machine that cuts in cycles ofmotion in mass production.
 19. The method of claim 15 comprising makingthe reservoir layer to have above 15 wt % galantamine and above 10 wt %permeation enhancer material in the reservoir layer.
 20. The method ofclaim 14 comprising making the reservoir layer and the first backinglayer to have flush edges and resulting in the device before deploymenton an individual at least one of the first backing layer edges havingmaterial from the first matrix adhering thereto.
 21. The method of claim20 comprising making the reservoir layer to have one or more permeationenhancers and galantamine is from 15 wt % to 35 wt % in the reservoirlayer and the one or more permeation enhancers and galantamineconstitute more than 30 wt % in the reservoir layer.
 22. The method ofclaim 15 further comprising cutting to provide a frame shape to thebarrier layer and attaching the framed shaped barrier layer to thesecond matrix layer on the second web.
 23. The method of claim 14further comprising machine-cutting the barrier layer with the firstbacking layer from a web.
 24. A method of making a device for deliveryof galantamine to an individual through a body surface, comprising: a.machine-cutting a reservoir layer and a first backing layer from a firstweb, the reservoir layer having a first matrix including galantamine at15 wt % to 35 wt % in the first matrix, the first backing layer beingsubstantially impermeable to galantamine, the reservoir layer beingattached to the first backing layer and has a reservoir layer outerperimeter; b. machine-cutting a second matrix layer from a second webhaving a second matrix material permeable to galantamine; c.machine-cutting a barrier layer from a web having a barrier materialthat is substantially impermeable to galantamine, the barrier layerhaving a barrier layer outer perimeter and having a window smaller thanthe outer perimeter of the reservoir layer outer perimeter; and d.adhesively affixing by machine the barrier layer intermediate thereservoir layer and at least part of the second matrix layer on a webincluding the second matrix layer, the reservoir layer outer perimeterbeing smaller than the barrier layer outer perimeter.
 25. A method ofmaking a device for delivery of galantamine to an individual through abody surface, comprising: a. machine-cutting a reservoir layer and afirst backing layer from a first web, the reservoir layer having a firstmatrix including galantamine, the reservoir layer and the first backinglayer to have flush edges and resulting in the device before deploymenton an individual at least some of the backing layer edges havingmaterial from the first matrix adhering thereto, the first backing layerbeing substantially impermeable to galantamine, the reservoir layerbeing attached to the first backing layer and has a reservoir layerouter perimeter, such that the first backing layer has a first backinglayer outer perimeter that is the same size as the reservoir layer outerperimeter; b. machine-cutting a second matrix layer and a second backinglayer from a second web, the second matrix layer being permeable togalantamine, the second backing layer having a second backing layerouter perimeter, the second matrix layer having a second matrix layerouter perimeter, such that the second backing layer outer perimeter isthe same size as the second matrix layer outer perimeter; c.machine-cutting a barrier layer from a web having a barrier materialthat is substantially impermeable to galantamine, the barrier layerhaving a barrier layer outer perimeter that is smaller than the secondmatrix layer outer perimeter and the barrier layer having a windowsmaller than the outer perimeter of the reservoir layer outer perimeter;and d. adhesively affixing by machine the barrier layer intermediate thereservoir layer and at least part of the second matrix layer on a webincluding the second matrix layer, the reservoir layer outer perimeterbeing smaller than the barrier layer outer perimeter.